Our goal is to elucidate the molecular mechanisms by which the haloethylenes, such as vinyl chloride, 1,1-dichloroethylene, and trichloroethylene, cause acute liver injury and aberrations in genetic material. The toxicity of haloethylenes is due to their biotransformation to reactive species capable of altering cell macromolecules. Haloethylene toxicity and biotransformation can be modulated by pretreatments which have a variety of effects, including induction of mixed function oxidase components particularly cytochrome P-450, or alterations in the availability of glutathione or changes in the intercellular levels of reducing equivalents. Use of such pretreatments can facilitate characterization of the biologic responses and metabolic products involved in the injurious interactions between reactive haloethylene species and cell macromolecules. Acute hepatic injury will be characterized by a multifaceted chemical, enzymatic and morpholoic approach. Cytogenetic studies will be carried out directly on the bone marrow and where possible on isolated hepatocytes from haloethylene exposed animals. Urine, bile and blood of haloethylene exposed animals, as well as haloethylene metabolites isolated from these fluids, will be assayed for mutagenicity by a variety of indicators. Haloethylene biotransformation will be monitored in whole animals, in isolate hepatocytes, and in cell fractions, and metabolites including covalently bound macromolecules will be isolated and identified. Relationships will be sought between injury and specific metabolic products. Patterns of metabolite production indicative of injurious metabolic pathways will be sought in animals in order to develop non-invasive methods to screen for haloethylene injury in man.